The Mediator complex allows communication between transcription factors and RNA polymerase II (RNAPII). Cyclin-dependent kinase 8 (CDK8), the kinase found in some variants of Mediator, has been characterized mostly as a transcriptional repressor. Recently, CDK8 was demonstrated to be a potent oncoprotein. Here we show, using a human tumor cell line, that CDK8 is a positive regulator of genes within the serum response network, including several members of the activator protein 1 and early growth response family of oncogenic transcription factors. Mechanistic studies show that CDK8 is not required for RNAPII recruitment or promoter escape. Instead, CDK8 depletion leads to the appearance of slower elongation complexes carrying hypophosphorylated RNAPII. CDK8-Mediator regulates precise steps in the assembly of the RNAPII elongation complex, including the recruitment of positive transcription elongation factor b and BRD4. Furthermore, CDK8-Mediator specifically interacts with positive transcription elongation factor b. Thus, we have uncovered a role for CDK8 in transcriptional regulation that may contribute to its oncogenic effects.
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